Abstract DP324: The NLRP3 inflammasome inhibitor, MCC950, mitigates cognitive impairment in a mouse model of vascular cognitive impairment and dementia (VCID)

Background: VCID and cerebral small vessel disease (CSVD) are the second leading cause of dementia. There is evidence that inflammation plays a role in VCID and CSVD. We hypothesized that inhibiting the NLRP3 inflammasome with the specific inhibitor, MCC950, would improve cognition and CBF in a mouse model of VCID. Methods: Middle-young C57BL/6 male mice (4-5 months old, male N=10-12/group) were subjected to bilateral carotid stenosis (BCAS model). Mice were randomly assigned to Sham, BCAS + placebo, or BCAS+MCC950 (10 mg/kg IP daily for 3 days and then every alternate day for 4 weeks) groups. We measured cerebral blood flow (CBF) via laser speckle contrast imaging (LSCI). Cognitive and motor functions were assessed using novel object recognition (NOR) and wire-hanging tests. Biochemical and histopathological analyses were also performed on brain tissues. Results: MCC950 improved cognition as measured by the NOR (Fig. 1A) and improved motor ability by the Beam Walk test (Fig. 1B). MCC950 also improved CBF compared to the placebo group (Fig. 2A&B). Moreover, biochemical and histopathological changes in the treatment group showed a significant (p<0.05) difference compared to the placebo group. Conclusions: These findings suggest that the NLRP3 inflammasome inhibitor, MCC950, mitigates cognitive impairment and motor deficits in the BCAS model and also significantly improves cerebral blood flow. This research highlights the potential of NLRP3 inflammasome inhibitors as a treatment for human VCID and CSVD.